3-mono and 20-mono-oximes of 11beta-hydroxy-5beta-pregnane-3, 20-dione and their corresponding 11alpha-methyl, 11alpha-allyl and 11alpha-methallyl derivatives



United States Patent O 3,012,046 3-MONO AND 20 MONO OXIMES OF 115 HY- DROXY-55-PREGNANE-3,ZG-DIONE AND THEIR CORRESPONDING 11a METHYL, 11a ALLYL 'AND Ila-METHALLYL DERIVATIVES William J. Wechter and Louis C. Schroeter, Kalamazoo, and Donald R. Buhler, Portage Township, Kalamazoo County, Mich., assignors to The Upjohn Company,

Kalamazoo, Mich, a corporation of Delaware No Drawing. Filed Mar. 28, 1961, Ser. No. 98,790 11 Claims. (Cl. 260397.45)

The present invention relates to new steroid compounds and is more particularly concerned with the 3-monoand 20-mono-oximes of 1lfl-hydroxy-Sfi-pregnane,20-dione and their corresponding Ila-methyl, lla-allyl and 11amethallyl derivatives.

The new compounds and processes of this invention are illustratively represented by the following formulae:

- on; CH3

HON-

wherein R is selected from the group consisting of hydrogen, methyl, allyl and methallyl.

The compounds of the present invention, i.e., the 3- monoand 20-mono-oximes of 11 B-hydroxy-SB-pregnane- 3,20 dione, lla methyl-l15-hydroxy-5fl-pregnane-3,20- dione, 1lat-allyl-llB-hydroxy-5B-pregnane-3,20-dione and 11a. methallyl-l lfi-hydroxy-SB-pregnane-S,20-dione, are central nervous system depressants useful as tranquilizers, muscle relaxants and sedatives in the treatment of hypertension, nervous disorders and related illnesses in both humans and valuable domestic animals. These compounds exist and can be used in both hydrated or anhydrous form.

The compounds of the present invention can be prepared and administered to mammals, birds, humans and animals in a wide variety of oral and parenteral dosage forms, singly, or in admixture with other coacting compounds. They can be associated with a carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed or suspended. The solid compositions' can take the form of tablets, powders, capsules, pills, or thelike, preferably in unit dosage forms for simple administration or precise dosages. The liquid compositions can take the form of solutions, emulsions, suspensions, syrups, or elixirs.

3,012,046 Patented Dec. 5, 1961 The 3,20-dione 3-mono-oxide compounds (I) of the present invention are prepared from their corresponding 3,20-diketo compounds (A) by 3-mono-oximation, e.g., by reaction with a hydroxylamine mineral acid salt in an acid medium.

Starting materials employed in the process for preparing the 3-mono-oxides of the present invention are the known 1l,8-hydroxy-5fl-pregnane-3,20-dione (J. Amer. Chem. Soc. 75, 486 [1953] 1la-methyl-llfi-hydroxy-Sfi-pregname-3,20-dione (synthesized in the manner described in U.S. Patent 2,944,069), 1la-allyl-llfl-hydroxy-Sfi-pregname-3,20-dione (prepared as in Example 3 of US. Patent 2,897,198), and 1lot-methylallyldlit-hydroxy-Sfi-pregnane-3,20-dione (prepared as in Example 4 of US. Patent 2,897,198).

The process of this invention for the production of 3- mono-oximes differs considerably from the method commonly employed in the preparation of 3,20-dione bis-' oximes. The 3-mono-oximes of the present invention as well as the 3,20-bisoximes produced by the usual method are both prepared from their corresponding 3,20-

' diketo compounds. by reaction with a hydroxylamine' mineral acid salt, but unlike the process for the preparation of 3,20-bisoximes, wherein basic solvents such as pyridine, collidine, N,N-dimethylaniline and the like are utilized, these basic solvents are avoided in the present invention andthe reaction is carried out instead in an acid medium. Also, in the present 3-mono-oxime process approximately equimolar equivalents of steroid compound and hydroxylamine mineral acid salts are employed, while in the conventional 3,20-bisoximes process an excess of hydroxylamine, usually from two to six molar equivalents is preferred.

The 3-mono-oximation reaction is preferably carried out at 20 to 120 C., and conveniently at the reflux temperature of the reaction mixture. Under these conditions the reaction time is usually from 15 minutes to 8 hours. Both higher and lower temperatures and shorter and longer reaction times are operative, the lower temperature usually requiring a correspondingly longer reaction time.

The 11}? hydroxy 5B 4 pregnane-3,20-dione 3-monooxime, 11cc methyl-11p-hydroxy5 3-pregnane-3,20-dione 3-mono-oxime, 1la-allyl-llfi-hydroxy-Sfi-pregnane 3,20- dione 3-mono-oxime and lla-methallyl-llfl-hydroxy-Sd pregnane-3,20-dione S-mono-oxime, thus produced, can be isolated from the reaction mixture by conventional methods, for example, when a water-missible solvent is used, by pouring the reaction mixture into water and separating the resultant precipitate by filtration. Additionalpurification oftheproduct can be accomplished by conventional methods, for example, by single solvent elution' chromatography from an adsorbent column with a suitable 5fi-pregnane-3,20-dione bisoxime (synthesized in the mansolvent, vsuch as, acetone, methanol, dilute methanol, ethanol, ether, methylene chloride; also by gradient elution chromatography from an adsorbentcolumn with'a,

suitable mixture of solvents, such as, methylene chloride- Skellysolve B (hexanes), acetone-Skellysolve B, and the like.

The 20-mono oxide compounds (H) of the present invention are prepared from the corresponding 3,20-bisoxirnes (B) by 3-deoximation, e.g., by reaction with an m-keto acid (a compound containing the monovalent CO-COOH radical).

Startingmaterials employed in the process for preparing the 20-mono-oxinies 'of the present invention are 11::- methyl 11 3 hydroxy-5fl-pregnane-3,ZO-dione bisoxime (prepared in the manner disclosed in the copending applitemperature of the reaction mixture.

ner disclosed below in Preparation 1), and llu-methallyl- 1lp-hydroxy-5p-pregnane-3,ZO-dione bisoxime (synthesized in the manner disclosed below in Preparation 2).

The process of the present invention for preparing the 20-mono-oxime compounds comprises treating the corresponding 3,20-bisoximes with an a-keto acid such as ocketopropionic acid (pyruvic acid), a-ketobutyric acid, ketophenylpropionic acid and the like, in a suitable solvent such as formamide or dimethylformamide.

The 3-deoximation reaction is preferably carried out about 20 to about 120 C., and conveniently at the room Under these conditions the reaction time is usually from about 15 minutes to about 12 hours. Both higher and lower temperatures and shorter and longer reaction times are operative, the lower temperature usually requiring a correspondingly longer reaction time.

The 115 hydroxy 5 3 pregnane 3,20 dione 20- mono-oxime, 11a methyl 1113 hydroxy 5 8 pregnane 3,20 dione 20 mono oxime, 11m allyl 1113- hydroxy 5,3 pregnane 3,20 dione 20 mono-oxime and 11a methallyl 11p hydroxy 55 pregnanc- 3,20 dione 20 mono-oxime, thus produced, can be isolated from the reaction mixture by conventional methods, for example, by pouring the reaction mixture into water and separating the resultant precipitate by filtration. Additional purification of the product can be accomplished by conventional methods, for example, by single solvent elution chromatography from an adsorbent column with a suitable solvent, such as, methanol, acetone, dilute methanol, ethanol, ether, methylene chloride; also by gradient elution chromatography from an adsorbent column with a suitable mixture of solvents, such as, methylene chloride-Skellysolve B (hexanes), acetone-Skellysolve B, and the like.

PREPARATION 1 1 1 a-allyl-J 1 fi-hydroxy-fi'B-pregnane- 3,20-dione bisoxime (B) A mixture of 10 g. of 1la-allyl-llfl-hydroxy-Sfi-pregnane-3,20-dione bis(ethylene ketal) (prepared in the manner disclosed in Example 1 of US. Patent 2,897,198) and 10 g. of hydroxylamine hydrochloride in 50 ml. of dry pyridine and 50 ml. of absolute ethanol was heated to reflux temperature for a period of about 6 hours. The solution thus obtained was then poured into 1.5 l. of ice water and refrigerated for a period of about three hours. The precipitate thus obtained was collected on a sintered glass funnel, washed thoroughly with water and dried in a vacuum oven giving crude lla-allyl-llfi-hydroxy-5 8-pregnane-3,20-dione bisoxime, a White solid. The crude product was then recrystallized from methylene chloride-Skellysolve B hexanes giving 6.1 g. (70% yield) of 1 la-allyl-l 16-hydroxy-5fi-pregnane-3 ,20-dione bisoxime melting at 148 to 154 C. A second crop of 990 mg. (11% yield) of crystals of lla-allyl-llfl-hydroxy-5fi-pregnene-3,20-dione bisoxime was obtained. An analytical sample was prepared by recrysta'llizing the productof the principal crop twice from methylene chloride, giving pure 1la-allyl-l1fl-hydroxy-5B-pregnane- 3,20-dione bisoxime (B) having a melting point of 155- 160 C. and infrared absorption maxima at 3520, 3300 511., 3240, 3120, 1 673 sh., 1663, 1635, 997, 963, 943, 927, 915, 897, and 893 cmf' PREPARATION 2 I] a-methally l-1 1 B-hydroxy-S fi-pregnane 3,20-di0ne bisoxime (B) procedure of Preparation 1, to obtain 11a-methal1yl-11p-.

4 hydroxy-SB-pregnane-S,20-dione bisoxime (B), a lightcolored crystalline solid.

EXAMPLE 1 11 a-methyl-l 1,6Jzydroxy-SB-pregnane- 3,20-dione 3-oxime (I) A solution of 695 mg. (0.01 mole) of hydroxylamine hydrochloride in about 5 ml. of water was added to 3.46 g. (0.01 mole) of lloc-Il'lCthYl-l lfi-hydroxy-Sfi-pregnane-3,20-dione (A) dissolved in about ml. of alcohol. The resulting solution was heated to reflux for a period of about 30 minutes and then allowed to remain at room temperature for about 18 hours. The reaction mixture was poured into water and the product allowed to solidify. The solid material was washed thoroughly by grinding in a mortar with water and dried at 60 C. in vacuo;

yield 3.0 g., melting point 89 to 102 C. (decomposition).

This material was recrystallized from ethanol-water at room temperature to give colorless leaves with a melting point of 109 to 114 C. (decomposition) and a yield of 1.67 g. This compound, 1la-methyl-lIB-hydroxy-SB- pregnane-3,20-dione 3-oxime (I), was recrystallized to provide an analytical sample and had a melting point of 109.0 to 114.0 C. (decomposition) and an infrared spectrum consistent with its proposed structure; its optical rotatory dispersion exhibited a strong positive cotton effect (indicative of a free 20-ketone) and its nuclear magnetic resonance confirmed that the structure of the compound contained 21-CH and 20-carbonyl functions. Bush A papergram of the compound showed essentially a single spot.

Analysis.Calcd. for C22H35O3N1/2H2OI C, 71.36; H, 9.79; N, 3.78; H O, 2.50. Found: C, 71.49; H, 9.61; N, 3.75; H O (Karl Fischer) 2.65.

Heating the hydrated compound in a vacuum oven yielded the corresponding anhydrous compound with the empirical formula: C H O N.

Following the procedure of Example 1 but substituting for the starting 1ltx-methyl-llfi-hydroxy-SB-pregnane- 3,20-dione (A) other 1la-lower-alkyl-l1fi-hydroxy-5;3- pregnane-3,20-diones (A), is productive of the correspondin g 1 1 a-lower-alkyl-l 1 fi-hydroxy-S fi-pregnane-El ,20- dione 3-oximes (I).

EXAMPLE 2 11B-hydroxy-Sp-pregnane-3,20-di0ne 3-oxime (I) Following the procedure of Example 1, but employing 11 8-hydroxy-5 3-pregnane-3,20-dione (A) (Oliveto et al.,

J. Amer. Chem. Soc., 75, 486 [1953]) as starting ma terial, is productive of 11fi-hydroxy-5fi-pregnane-3,20- dione 3-oxime (I).

EXAMPLE 3 1 1 a-allyi-l 1 [i-hydroxy-Sfi-pregnane- 3,20-di0ne 3 -oxime (I) Following the procedure of Example 1, but employing 1 la-allyl-l 1fl-hydroxy-5fl-pregnane-3,20-dione (A) (prepared in the manner disclosed in Example 3 of 11.5. Patent 2,897,198) as starting material, is productive of 11cc allyl 116 hydroxy 5a pregnane 3,20 dione 3-oxime (I).

EXAMPLE 4 1 1 a-methallyl-l Jfi-hydroxy-SB-pregnane 3,20-dione 3-oxime (I) Following the procedure of Example 1, butemploying 11oz methallyl 115 hydroxy 5e pregnane 3,20- dione (A) (prepared in the manner disclosed in Example 4 of US. Patent 2,897,198) as starting material, is prodione 3-oxime (I).

EXAMPLE 5 11oz methyl 11p hydroxy 5/3 pregnzme 3,20 dione -oxime (II) Ten ml. of 50% aqueous pyruvic acid was added under nitrogen to a solution of 4.8 g. of llct-methyl-llfi-hydroxy-SB-pregnane-S',ZO-dione bisoXime (B) in 20 ml. of dimethylformamide. Brief warming yielded a solution which was allowed to stand at room temperature for about 18 hours. This material was then poured into 250 ml. of Water and the crude amorphous solid isolated, ground in a mortar with water, Washed and dried in vacuo at a temperature of about 60 C. The product was isolated by pouring it on a column or" Florisil (synthetic magnesium silicate) and employing gradient elution chromatography with mixtures of solvents composed of from 5 to 50% acetone in Skellysolve B (hexane hydrocarbons). The isolated product was crystallized from ethanol-Water and gave a white crystalline solid, Ila-methyl- 1B-hydroxy-Sfl-pregnane-B,ZO-dione 20-0Xime (II), having an infrared spectrum showing a strong OH (broad) band, CO (1700 cm.--) and oxime bands (ca. 900 cm. no strong positive cotton effect curve Was exhibited by optical rotatory dispersion (indicative of 20- ketone oximation) Following the procedure of Example 5 but substituting for the starting lla-methyl-l1fi-hydroxy-5fl-pregnane-3, ZO-dione bisoxime (B) other lla-lower-allyl-l LB-hydroxy-Sfi-pregnane-Zl,ZO-dione bisox irnes (B) is productive of the corresponding 1la-lower-alkyl-lIfl hydrOXy- 5fi-pregnane-3,20-dione 3-0Ximes (II).

EXAMPLE 6 11B-hydr0xy-5B-pregnane-3,20-di0ne 20-0xime (II) Following the procedure of Example 5, but employing 11B-hydroXy-5fl-pregnane-3,ZO-dione bisoXime (B) as starting material, is productive of llfi-hydroxy-Sfi-pregnane-3,20-dione 20-oxime (II).

EXAMPLE 7 11oz allyl 11B hydroxy 5,8 pz-egnane 3,20 dione I 20-oxime (II) Following the procedure of Example 5, but employing 11cc allyl 11B hydroxy 5,3 pregnane 3,20- dione bisoxime (B) (obtained as in Preparation 1) as starting material, is productive of llu-allyl-llfi-hydroxy-SB-pregnane-3,20-dione 20-oXime (II).

EXAMPLE 8 11a methallyl 11B hydroxy 55 pregnane 3,20 dione ZO-Oxime (II) Following the procedure of Example 5, but employing 110: methallyl 115 hydroxy 5,8 pregnane 3,20- dione bisoxime (B) (obtained as in Preparation 2) as starting material, is productive of 11a-methallyl-11B-hydroxy-Sfi-pregnane-F;,ZO-dione ZO'OXIHIK: (II).

We claim: 1. 11/3-hydroXy-5/3-pregnane-3,ZD-dione 3-oximes of the formula HON- 7. 11B-hydroxy-Sfi-pregnaned,ZO-dione 20-0Ximes of the formula wherein R is selected from the group consisting of hydrogen, methyl, allyl and methallyl.

8. 11fi-hydroxy-SB-pregnane-3,ZO-dione ZO-oxime.

9. 1lwmethyl-llfi-hydroxy-Sfi-pregnane-S,ZO-dione 20- oxirne.

10. allyl 11,8 hydroxy 5,8 pregnane 3,20- dione 20-oXime.

11. 110: me-thallyl hydroxy 5,3 pregnane 3, 20-dione 20-o ime.

References Cited in the file of this patent UNITED STATES PATENTS Tendrick et a1. Nov. 30, 1943 Hershberg Aug. 17, 1948 OTHER REFERENCES Oliveto et al.: J.A.C.S., vol. 78, 1736-38 (1956),

UNITED STATES PATENT oFFIcE CERTIFICATE OF CORRECTION Patent No. 3 Ol2,046 December 5 1961 William J, Wechter et al.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line l for "3-mono-oxide" read 3-monooxime; line 7 for "3-m0no-oxides" read 3mono-oximes line 59, for '2Omono--oxides" read 20monooxime column 6, lines 30 to 39, the formula should appear as shown below instead of as in the patent: CH3

I C NOH Signed and sealed this 8th day of May 1962 (SEAL) Attest:

ERNEST W. SWIDER Attesting Officer DAVID L. LADD Commissioner of Patents 

1. 11B-HYDROXY-5B-PREGNANE-3,20-DIONE 3-OXIMES OF THE FORMULA 